Kidney Damage

Kidney Damage Associated With Gentamicin Use

Gentamicin is toxic to certain kidney cells. It is excreted in the urine, which results in the kidney cells of a person being treated with gentamicin being almost constantly bathed in gentamicin. When gentamicin is given for too long, or at too high a dose, progressive kidney failure frequently occurs. As the kidneys fail, less gentamicin is excreted. This leads to a higher concentration of gentamicin in the bloodstream, which may further damage the kidneys. Once the kidney begins to fail in a person receiving gentamicin, further kidney damage may quickly ensue if the gentamicin dose is not adjusted or discontinued. Kidney failure induced by gentamicin is often reversible, or partially reversible, unlike most of gentamicin’s side effects.

 

Symptoms of Kidney Damage

According to Mayoclinic.com, signs of kidney damage can include:

  • Decreased urine output, although occasionally urine output remains normal
  • Fluid retention, causing swelling in your legs, ankles or feet
  • Drowsiness
  • Shortness of breath
  • Fatigue
  • Confusion
  • Seizures or coma in severe cases
  • Chest pain related to pericarditis, an inflammation of the sac-like membrane that envelops your heart

However, most people who are on gentamicin do not experience these symptoms until late in the process. Therefore, it is critical that kidney function be measured to detect early nephrotoxicity at least weekly, and preferably every 3 days, when taking gentamicin.

 

How Kidneys Function

To more fully comprehend how gentamicin affects the kidney, it helps to understand normal kidney function. Basically, the kidneys filter blood and create urine. Blood flows from the aorta through the renal artery to the kidney, where the blood is filtered, and then flows back through the renal vein to the inferior vena cava. The urine is carried out of the kidney by tubes called ureters, and is held in the urinary bladder until emptied. A diagram of the gross anatomy of the kidney in relation to the body as a whole is shown in Figure 1.

 

A cutaway diagram of the kidney is shown in figure 2.

Once the blood flows through the renal artery and enters the kidney, it branches down to smaller and smaller arterioles until it enters capillaries, or very tiny microscopic blood vessels, which consist of a wall that is only one cell thick. These specialized capillaries are organized to form glomerulii, which are the outer layers of the Malpigian corpuscles. These are located near the surface of the kidney. Inside of each glomerulus is an epithelial Bowman's capsule. If one looks at the microscopic structure of a Malpigian corpuscle, there is a very thin membrane separating the blood inside of the glomerular capillaries and the Bowman’s capsule, which contains the precursor of urine. (Figure 3).

 

It is here where the initial filtration of blood takes place. Because of the pressure gradient formed across this membrane, water molecules and smaller dissolved molecules in the blood flow across the membrane into Bowman’s capsule. Blood cells and large molecules like proteins are kept inside of the capillary and returned to the bloodstream. This process of initial filtration is passive, and is dependent only on the pressure gradient formed across the glomerular membrane. The precursor urine filtered into Bowman’s capsule is known as glomular filtrate

 

The Bowman’s capsule joins a series of tubules starting with the proximal tubule and followed by the loop of Henle, the distal tubule, and ending in the collecting ducts. (Figure 4) .

The glomular filtrate travels through a long, thin tubule, (proximal tubule), that goes from Bowman’s capsule toward the center of the kidney, forms a hairpin turn, (loop of Henle), and travels back out toward the surface of the kidney through another long, thin tubule, (distal tubule). The distal tubule then empties into small collecting ducts that branch into larger collecting ducts that come together in the center of the kidney to form a small reservoir called a calyx, which drains into the ureter. The proximal and distal tubules are surrounded by blood capillaries. During its flow from Bowman’s capsule through the proximal tubule, loop of Henle, distal tubule and collecting tubules, the glomular filtrate is further processed by losing water and certain molecules back to the bloodstream, and gaining other molecules from the bloodstream. A portion of this transport process is controlled by osmotic pressure gradients, and a portion is the result of active transport across cell membranes. By removing water but not certain molecules from the glomular filtrate as it is processed, these molecules become concentrated, facilitating their excretion but preserving water.

 

Through this process, a much greater volume of glomular filtrate is produced at any given time period than urine is produced. The rate at which glomular filtrate is produced is known as the glomular filtration rate, (GFR). GFR is a very important measure of kidney function. While GFR cannot be conveniently measured directly, it can be estimated from the amount of a metabolic byproduct, (creatinine) that is excreted in the urine during a 24 hour period. This is known as the creatinine clearance rate, or CrC. Creatinine a metabolic byproduct that is delivered to the bloodstream at a fairly constant rate. It is filtered from the blood into the precursor urine in the glomerulus. Creatinine is not significantly reabsorbed or secreted by the renal tubules. Therefore, the amount of creatinine excreted in the urine every day parallels the daily amount of glomular filtration. Various studies have correlated measured glomular filtration with measured creatinine clearance. Measuring true CrC requires every bit of a patient’s urine to be collected for 24 hours, and then measuring the creatinine concentration in the blood and the collected urine. Studies have shown that the GFR can be closely estimated by a formula using the patient’s age, sex, weight in kilograms, and the serum creatinine level. (This formula assumes a relatively steady state of kidney function, which is not usually the case in acute gentamicin poisoning.)

The formula for determining GFR in milliliters per minute is:

(140-age) x (weight)/72 x SCr

 

(For women, these results must be multiplied by 0.85.)

Where:

1. SCr is serum creatinine level in mg/dl

2. Age is in years

3. Weight is in kg

As an example, a 50 year old male weighing 220 lbs., (100 kg), with a serum creatinine level of 0.8 mg/dl would have a GFR of 90 x 100 divided by 72 x 0.8, which equals 156 ml/minute. Therefore, for a given person over a short period of time where age and weight don’t change, kidney function is roughly inversely proportional to the level of serum creatinine. If this same man’s SCr rose to 1.6 mg/dl, one could assume that his GFR had dropped to about 78 ml/min.

Gentamicin acts much the same as creatinine when it is excreted. Gentamicin freely diffuses across the glomular wall to the glomular filtrate. Within certain limits, if the GFR is decreased by 50%, only 50% as much gentamicin will be eliminated as before the decrease, but the concentration of gentamicin in the GFR will remain the same. If there is no change in the amount of gentamicin being infused into the bloodstream each day, the gentamicin will accumulate in the blood, and the serum concentration of gentamicin will go up. As the serum concentration of gentamicin goes up, so does the concentration of gentamicin in the GFR. Because gentamicin is toxic to the kidneys, an increased gentamicin concentration means that even more of the kidney cells are damaged, less glomular filtrate is formed, and the serum concentration of gentamicin goes up even further. Therefore, monitoring kidney function by monitoring SCr is considered very important not only before initiating gentamicin therapy, but periodically after the therapy has begun. As the serum concentration of gentamicin goes up, there is increasing risk of damage to the vestibular system. Thus, uncorrected or unnoticed kidney failure in a person receiving gentamicin is often quickly followed by ototoxicity.

Set forth here is a very simple explanation of kidney function. It omits many of the issues relevant to gentamicin-induced nephrotoxicity, (kidney poisoning). For more detailed information, please visit these Renal (Kidney) Physiology and Pathophysiology articles and resources.

 

Renal (Kidney) Physiology And Pathophysiology

  • How Your Kidney Works by Craig C. Frundenrich, PhD.. This is a good website with illustrations.
  • Brenner and Rector’s The Kidney, ed. Brenner, Barry (2000) W.B. Saunders Co., Philadelphia. A complete, two volume reference for everything you ever waned to know about renal function.
  • Renal Function A tutorial on renal function.

 

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